The Effects of ADHD Medication (TEAM) Study

The stimulant methylphenidate (MPH) is the most commonly prescribed psychoactive medication
in children. An abundance of studies attest to the efficacy of MPH for attenuating
inattentive, hyperactive, and impulsive symptoms in children with ADHD. Despite its
efficacy, most children with ADHD who are prescribed MPH have poor continuity of treatment
for a variety of reasons, including forgetting to administer the medication and delays
obtaining refills. In addition, it is an accepted clinical practice for physicians to omit
MPH for periods of time, such as during the summer or on weekends (i.e., drug holidays).
Since MPH discontinuation is considered to be benign, many clinicians do not employ any
special procedures or inform families of any special precautions in regard to its cessation.
However, increasing evidence suggests that the pharmacological effects of MPH cause lasting
changes in brain neurochemistry that persist beyond medication discontinuation. Moreover,
these neurobiological effects of discontinuation appear to have neurobehavioral
consequences. There is a critical need to better understand the breadth and magnitude of the
neurobehavioral effects caused by MPH discontinuation as well as to better understand the
temporal trajectory of these deleterious effects. Hence, the primary goal of the proposed
research is to conduct the first randomized, double-blind, placebo-controlled trial
specifically designed to study the negative effects of MPH discontinuation at multiple time
points. 180 children diagnosed with ADHD will participate across two recruitment sites.
After undergoing a 4-week MPH titration trial and 4-week MPH maintenance phase, participants
will be randomized to either discontinue MPH (and receive placebo) OR remain on MPH for 4
weeks. Comprehensive multi-time point, multi-informant (parents, teachers, study staff) and
multi-modal (behavior/mood/affect ratings scales, direct behavior observations, standardized
testing) assessments will be used to assess a broad range of neurobehavioral outcomes. We
will examine the magnitude and time course of effects of MPH discontinuation on behavioral
as well as cognitive and academic functioning in children with ADHD. Furthermore, we will
examine moderators of the adverse effects of MPH discontinuation on these outcomes to aid in
the identification of those who are at increased risk.

Inclusion Criteria:

1. ADHD Diagnostic Status: Meets DSM-V criteria for ADHD, with Clinical Global
Impression (CGI) rating corresponding to at least "moderately ill."

2. Cognitive and Academic Functioning: Intelligence Quotient (IQ) of >80 as estimated by
Vocabulary and Block Design subtests of the Wechsler Intelligence Scale for
Children-4th Edition and scaled scores >80 on the Wechsler Individual Achievement
Test-2nd edition Reading and Math subtests

3. Physical Health: Physical exam and ECG findings are judged to be normal for age and
sex by study physician and/or medical consultant, and there is no co-existing
condition for which MPH is contraindicated 4. School: Enrolled in a school setting
rather than a home-school program. This ensures that we can obtain parent and teacher
ratings from separate individuals for diagnosis and outcome assessment

Exclusion Criteria:

1. Psychiatric Medications: Current or prior use of any medication for
psychological/psychiatric problems

2. Behavioral Interventions: Current active participation in ADHD-related behavioral
interventions, given that improvements due to these interventions may confound our
group comparisons

3. Psychiatric or Neurobehavioral Conditions: Children with mania/hypomania,
schizophrenia, or severe depressive disorder, as determined by the K-SADS, will be
excluded since ADHD medications may not be an appropriate first line of treatment for
children with these comorbid disorders

4. Organic Brain Injury: History of head trauma, neurological disorder (including
epilepsy), or other disorder affecting brain function due to potential differences in
neurophysiology of ADHD phenotype

5. Cardiovascular Risk Factors: Children with a personal history or family history of
cardiovascular risk factors will be excluded, or given the option of participating in
the study after obtaining an EKG and verification from a pediatric cardiologist
regarding the safety of their participation in a trial of methylphenidate. In this
case, families will be responsible for the costs of EKG and any necessary
cardiologist evaluation

6. Pregnancy: The safety of MPH use during pregnancy has not been established